Rac GTPases regulate the actin cytoskeleton to control changes in cell shape. To date, the analysis of Rac function during development has relied heavily on the use of dominant mutant isoforms. Here, we use loss-of-function mutations to show that the three Drosophila Rac genes, Rac1, Rac2 and Mtl, have overlapping functions in the control of epithelial morphogenesis, myoblast fusion, and axon growth and guidance. They are not required for the establishment of planar cell polarity, as had been suggested on the basis of studies using dominant mutant isoforms. The guanine nucleotide exchange factor, Trio, is essential for Rac function in axon growth and guidance, but not for epithelial morphogenesis or myoblast fusion. Different Rac activators thus act in different developmental processes. The specific cellular response to Rac activation may be determined more by the upstream activator than the specific Rac protein involved.
Growth, guidance and branching of axons are all essential processes for the precise wiring of the nervous system. Rho family GTPases transduce extracellular signals to regulate the actin cytoskeleton. In particular, Rac has been implicated in axon growth and guidance. Here we analyse the loss-of-function phenotypes of three Rac GTPases in Drosophila mushroom body neurons. We show that progressive loss of combined Rac1, Rac2 and Mtl activity leads first to defects in axon branching, then guidance, and finally growth. Expression of a Rac1 effector domain mutant that does not bind Pak rescues growth, partially rescues guidance, but does not rescue branching defects of Rac mutant neurons. Mosaic analysis reveals both cell autonomous and non-autonomous functions for Rac GTPases, the latter manifesting itself as a strong community effect in axon guidance and branching. These results demonstrate the central role of Rac GTPases in multiple aspects of axon development in vivo, and suggest that axon growth, guidance and branching could be controlled by differential activation of Rac signalling pathways.
Drosophila atonal (ato) is the proneural gene of the chordotonal organs (CHOs) in the peripheral nervous system (PNS) and the larval and adult photoreceptor organs. Here, we show that ato is expressed at multiple stages during the development of a lineage of central brain neurons that innervate the optic lobes and are required for eclosion. A novel fate mapping approach shows that ato is expressed in the embryonic precursors of these neurons and that its expression is reactivated in third instar larvae (L3). In contrast to its function in the PNS, ato does not act as a proneural gene in the embryonic brain. Instead, ato performs a novel function, regulating arborization during larval and pupal development by interacting with Notch.
Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.
We present a method to leverage radical for learning Chinese character embedding. Radical is a semantic and phonetic component of Chinese character. It plays an important role as characters with the same radical usually have similar semantic meaning and grammatical usage. However, existing Chinese processing algorithms typically regard word or character as the basic unit but ignore the crucial radical information. In this paper, we fill this gap by leveraging radical for learning continuous representation of Chinese character. We develop a dedicated neural architecture to effectively learn character embedding and apply it on Chinese character similarity judgement and Chinese word segmentation. Experiment results show that our radical-enhanced method outperforms existing embedding learning algorithms on both tasks.
Prostate cancer (PCa) represents one of the most common solid neoplasms, and metastasis is the second leading cause of death in adult males. Anoikis is a programmed cell death that is induced upon cell detachment from the extracellular matrix (ECM), which behaves as a critical protective mechanism for anchorage-independent cell growth and metastasis formation. However, in the absence of ECM attachment, shift of metabolic pattern and tolerance to anoikis facilitate the survival of aggressive cancer cells in the circulatory system as well as their metastasis to distant sites. Few molecular targets in PCa have thus far been reported to prevent anoikis resistance, metabolic reprogramming, and metastasis simultaneously. In the present study, elevated migration, invasion, pyruvate production, lactate generation, ATP level, and impaired detachment-induced apoptosis were found in anoikis-resistant PCa cells, and genome microarray analysis demonstrated that the cell migration-inducing protein (CEMIP) was a potential molecular target for the regulation of the aforementioned malignant behaviors. Additional investigation revealed that the AMPK/glycogen synthase kinase 3β (GSK3β)/β-catenin cascade-triggered CEMIP overexpression in anoikis-resistant PCa cells might be implicated in local progression, metabolic shift, and cellular migration and invasion, whereas knockout of CEMIP by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 in anoikis-resistant PCa cells reversed the described bioeffects by reducing expressions of matrix metalloproteinase 2 (MMP2), VEGF, pyruvate dehydrogenase kinase isoform 4 (PDK4), and lactate dehydrogenase A. In addition, inhibition of glycolysis by CEMIP-mediated PDK4 down-regulation impaired the migration and invasion of anoikis-resistant PCa cells by attenuating MMP2 and VEGF expressions. Our findings establish that AMPK/GSK3β/β-catenin cascade-triggered CEMIP overexpression might promote migration and invasion in anoikis-resistant PCa cells by enhancing PDK4-associated metabolic reprogramming, which may provide a novel, promising therapeutic target for the treatment of advanced PCa.-Zhang, P., Song, Y., Sun, Y., Li, X., Chen, L., Yang, L., Xing, Y. AMPK/GSK3β/β-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming.
Proneural basic helix-loop-helix (bHLH) proteins initiate neurogenesis in both vertebrates and invertebrates. The Drosophila Achaete (Ac) and Scute (Sc) proteins are among the first identified members of the large bHLH proneural protein family. phyllopod (phyl), encoding an ubiquitin ligase adaptor, is required for ac-and sc-dependent external sensory (ES) organ development. Expression of phyl is directly activated by Ac and Sc. Forced expression of phyl rescues ES organ formation in ac and sc double mutants. phyl and senseless, encoding a Zn-finger transcriptional factor, depend on each other in ES organ development. Our results provide the first example that bHLH proneural proteins promote neurogenesis through regulation of protein degradation.E3 ligase ͉ senseless ͉ basic helix-loop-helix ͉ neurogenesis T he basic helix-loop-helix (bHLH) proneural proteins promote neurogenesis from flies to mammals (for reviews, see refs. 1 and 2). In Drosophila, the proneural proteins Achaete (Ac), Scute (Sc), Atonal (Ato), and Amos are bHLH transcriptional factors that are essential for the generation of neural precursors in the central and peripheral nervous systems (3-5). In mammals, the bHLH proteins Mash1, homolog of Ac and Sc, and Neurogenins, homologs of Ato and Amos, are essential for the initiation of neurogenesis (6, 7). Proneural genes are expressed in small clusters of cells, called proneural clusters, and they endow cells the potential to adopt neural fate, such as sensory organ precursors (SOPs) in the Drosophila peripheral nervous system. However, lateral inhibition mediated by the ligand Delta and the receptor Notch restricts the expression of proneural genes to only one or a few cells that differentiate into neural precursors, and prevents neighboring cells of the selected neural precursors from adapting the same fate (8).The Drosophila proneural genes ac and sc function redundantly in the formation of external sensory (ES) organs; in ac and sc double mutants, formation of ES organs is disrupted, and misexpression of either ac or sc induces ectopic ES organs (9-12). The Ac and Sc proteins share 70% identity in their bHLH domains (3), and form heterodimers with the ubiquitously expressed bHLH protein Daughterless (Da) to activate transcription of downstream target genes (13,14). One target gene of Ac and Sc, asense (ase), also encodes a bHLH protein that is specifically expressed in SOPs and involved in SOP differentiation (15-17). Likewise, NeuroD, the mammalian homolog of Ase, also plays an important role in neuronal differentiation (18). In addition to the bHLH genes, a number of Ac and Sc target genes have been identified. For example, senseless (sens) is expressed in SOPs and is required to maintain high levels of proneural proteins in SOPs (19,20). Genes involved in lateral inhibition to select SOPs are also targets for Ac and Sc, including scabrous (sca), Delta (Dl), and those in the Enhancer of split [E(spl)] and Bearded (Brd) complexes (21,22). However, target genes essential for SOP differentiation ...
Stork (2021): TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy, Autophagy,
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